Precision medicine is becoming considerably critical in colorectal cancer therapy. Particularly for targeted therapies, the response to anti-EGFR therapy largely varies among individual patients. The mechanisms of anti-EGFR-based regimens resistance have been revealed, for instance, mutations in KRAS, BRAF, and PIK3CA. It is well known that colorectal cancer is a heterogeneous disease, massive evidences indicate that there are intertumour and intratumour heterogeneities in colorectal cancer. Recently, the integrative factor of the genetic, epigenetic and microenvironmental alterations that attribute to CRC heterogeneity is associated with the response to targeted therapies. We review here the possible mechanisms of heterogeneity that influence the anti-EGFR therapy, and mainly focus on the enhancive biomarkers detection to predict the therapy efficiency and select appropriate patients who are most likely to benefit from special targeted therapies, and take advantage of simultaneously blocked the multiple molecules involved in activation of independent of ligands induced EGFR signaling pathway to overcome the resistance to anti-EGFR therapies.